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首页> 外文期刊>Nucleic Acids Research >The catalytic subunit DNA-dependent protein kinase (DNA-PKcs) facilitates recovery from radiation-induced inhibition of DNA replication.
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The catalytic subunit DNA-dependent protein kinase (DNA-PKcs) facilitates recovery from radiation-induced inhibition of DNA replication.

机译：催化亚基DNA依赖性蛋白激酶（DNA-PKcs）有助于从辐射诱导的DNA复制抑制中恢复。

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Exposure of cells to ionizing radiation inhibits DNA replication in a dose-dependent manner. The dose response is biphasic and the initial steep component reflects inhibition of replicon initiation thought to be mediated by activation of the S-phase checkpoint. In mammalian cells, inhibition of replicon initiation requires the ataxia telagiectasia mutated ( ATM ) gene, a member of the phosphatidyl inositol kinase-like (PIKL) family of protein kinases. We studied the effect on replicon initiation of another member of the PI-3 family of protein kinases, the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) by measuring either total DNA synthesis, or size distribution of nascent DNA using alkaline sucrose gradient centrifugation. Exposure of human cells proficient in DNA-PKcs (HeLa or M059-K) to 10 Gy inhibited replicon initiation in a time-dependent manner. Inhibition was at a maximum 1 h after irradiation and recovered at later times. Similar treatment of human cells deficient in DNA-PKcs (M059-J) inhibited replicon initiation to a similar level and with similar kinetics; however, no evidence for recovery, or only limited recovery, was observed for up to 8 h after irradiation. In addition a defect was observed in the maturation of nascent DNA. Similarly, a Chinese hamster cell line deficient in DNA-PKcs (irs-20) showed little evidence for recovery of DNA replication inhibition up to 6 h after irradiation, whereas the parental CHO cells showed significant recovery and an irs-20 derivative expressing the human DNA-PKcs complete recovery within 4 h. Normal kinetics of recovery were observed in xrs-5 cells, deficient in Ku80; in 180BR cells, deficient in DNA ligase IV; as well as XR-1 cells, deficient in XRCC4, an accessory factor of DNA ligase IV. Since all these cell lines share the DNA double strand break rejoining defect of M059-J and irs20 cells, the lack of recovery of DNA replication in the latter cells may not be attributed entirely to the prolonged presence of unrepaired DNA dsb. We propose that DNA-PKcs, in addition to its functions in the rejoining of DNA dsb and in DNA replication, also operates in a pathway that in normal cells facilitates recovery of DNA replication after irradiation.
机译：细胞暴露于电离辐射中会以剂量依赖性方式抑制DNA复制。剂量反应是双相的，初始陡峭成分反映了复制子启动的抑制作用，认为该复制子启动是由S期检查点的激活介导的。在哺乳动物细胞中，复制子启动的抑制需要共济失调突变（ATM）基因，它是磷脂酰肌醇激酶样（PIKL）蛋白激酶家族的成员。我们通过测量总DNA合成或使用碱性蔗糖测定新生DNA的大小分布，研究了PI-3蛋白激酶家族另一个成员（依赖DNA的蛋白激酶（DNA-PKcs）的催化亚基）对复制子启动的影响梯度离心。精通DNA-PKcs（HeLa或M059-K）的人类细胞暴露于10 Gy会以时间依赖的方式抑制复制子的启动。抑制作用在照射后最多1小时，并在以后恢复。对缺乏DNA-PKcs（M059-J）的人类细胞的类似处理将复制子的启动抑制到相似的水平，并且具有相似的动力学。然而，在照射后长达8小时，没有观察到恢复的证据，或只有有限的恢复。另外，在新生DNA的成熟中观察到缺陷。同样，缺乏DNA-PKcs（irs-20）的中国仓鼠细胞系几乎没有证据显示辐照后长达6 h恢复了DNA复制抑制，而亲代CHO细胞显示出明显的恢复并且表达了表达人类的irs-20衍生物DNA-PKcs在4小时内完全恢复。在缺乏Ku80的xrs-5细胞中观察到正常的恢复动力学。在180BR细胞中，缺乏DNA连接酶IV;以及缺乏XRCC4（DNA连接酶IV的辅助因子）的XR-1细胞。由于所有这些细胞系均具有M059-J和irs20细胞的DNA双链断裂再结合缺陷，因此后者细胞中DNA复制缺乏恢复可能并非完全归因于未修复的DNA dsb的延长存在。我们建议，DNA-PKcs，除了其在DNA dsb的重新结合和DNA复制中的功能外，还可以在正常细胞中促进辐射后DNA复制的恢复的途径中运作。

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